Background: No anti-cocaine medication will be universally effective because non-medication factors such as environmental conditions (e.g. alternatives to drug use) and individual differences (e.g. behavioral history) constrain the efficacy of any medication. Therefore, tests of cocaine medications need to be conducted in synchrony with behavior therapies also taking into account individual differences in order to understand the mechanisms of interaction and potential boundary conditions of a medication's efficacy. Approach: In this human laboratory model of cocaine treatment, we will investigate the ability of continuous and intermittent schedules of non-drug positive reinforcement ("Carrots";analogues of standard and prize-based contingency management [CM] treatment) and punishment ("Sticks";analogue of the adverse consequences of cocaine use) and a promising agonist-like medication for treatment of cocaine dependence (sustained release d- amphetamine [SR-AMP]) to alter cocaine demand using behavioral economic analyses. We will also prospectively explore two individual difference factors, level of cocaine use and severity of cocaine withdrawal symptoms, which may influence sensitivity to these effects. By conducting thematically integrated and parametrically organized studies (including systematic replications and extensions), we hope to understand how these factors interact (short term goal) and ultimately improve treatment efficacy for cocaine dependence (long term goal). Primary Aims: (1) Determine in a laboratory model of CM, using money as a non-drug alternative, whether: (a) higher- vs. lower-magnitude continuous positive reinforcement increases cocaine elasticity;(b) intermittent positive reinforcement conditions (which will be equated in magnitude with continuous reinforcement) differentially affect cocaine elasticity;and (c) cocaine demand is functionally equivalent at matched unit prices comprised of differing fixed ratio/unit dose combinations, (2) Determine whether (a) drug choice-contingent money loss (predictable punishment, relative to no punishment) increases cocaine elasticity, (b) higher vs. lower probabilities of punishment (equated for average magnitude of money loss) increase cocaine elasticity, and (c) the combination of higher (relative to lower) magnitude positive reinforcement and higher (relative to lower) probability of punishment additively increases cocaine elasticity. (3) Determine whether SR-AMP 15 mg BID (30 mg/day total) relative to placebo: (a) increases cocaine elasticity under minimally assisted conditions (i.e. low-magnitude non-drug reinforcement and absence of punishment), and (b) enhances the ability of positive reinforcement/punishment combinations to increase cocaine elasticity. Secondary Aim: Determine whether pre-experimental individual differences in cocaine use or withdrawal symptoms moderate the efficacy of positive reinforcement or punishment contingencies on cocaine demand. PUBLIC HEALTH RELEVANCE: As we develop medications for cocaine dependence, it is critical to investigate the extent to which non-drug (environmental and individual difference) factors influence medication efficacy. In this human laboratory model of cocaine treatment, we will programmatically examine the ability of continuous and intermittent schedules of non-drug positive reinforcement (money choice-contingent earnings) and punishment (drug choice-contingent money loss), in combination with oral sustained release d-amphetamine (vs. placebo), for reducing cocaine demand using behavioral economic analyses. We will also explore whether individual differences in cocaine use and withdrawal symptom severity influence sensitivity to these effects. Three thematically integrated and parametrically organized studies (including systematic replications and extensions) are intended to understand how these factors interact (short term goal) and to improve treatment efficacy for cocaine dependence (long term goal).